One of the most important goals in modern chemical biology and biomedical sciences is to identify molecular ligands that recognize peptides or proteins of interest with high specificity and affinity. These ligands can be used as invaluable biological tools, such as biomarkers for protein purification, detection and targeted imaging, or used as potential drug leads or candidates for therapeutic development. Combinatorial chemistry is a powerful approach for ligand screening, creating a diverse library of compounds, which provides unbiased opportunity for ligand identification when the structural information of targets is not available or not helpful in the rational design technique. In fact, most bioactive molecules are identified through screening efforts. Since peptides have favorable protein binding capabilities and are capable of modular synthesis, early efforts were dedicated to the identification of selective peptide ligands against a variety of targets.
However, natural proteins have drawbacks such as, but not limited to, instability due to susceptibility to proteolysis. Interest in unnatural peptidomimetic ligand libraries developed recently, as these ligands contain unnatural backbones and therefore possess enormous structural diversity and enhanced stability against proteolysis. The examples of peptidomimetic ligands include peptoids, β-peptides, and N-acylated polyamine, etc. However, except for peptoids, applications of such peptidomimetic ligand library are rare. Compared to novel therapeutic and tool ligands, the development of new peptidomimetic ligand libraries lags behind, due in part to the limited availability of backbones and functional diversity, as well as the difficulty in identification of lead compounds. Therefore, peptidomimetic libraries including ligands with novel backbones may facilitate identification of novel molecular probes and drug candidates.